猪-人胶质瘤异种移植模型。免疫抑制和模型重现性。

Q3 Medicine
P.Jack Hoopes , Armin D. Tavakkoli , Karen A. Moodie , Kirk J. Maurer , Kenneth R. Meehan , Diana J. Wallin , Ethan Aulwes , Kayla E.A. Duval , Kristen L. Chen , Margaret A.Crary -Burney , Chen Li , Xiaoyao Fan , Linton T. Evans , Keith D. Paulsen
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引用次数: 0

摘要

背景:胶质母细胞瘤是最常见的原发性恶性人类脑肿瘤,对治疗具有耐药性。啮齿动物模型在了解脑癌生物学和治疗方面发挥了重要作用。然而,由于啮齿动物的颅骨较小,肿瘤体积与人类疾病不匹配,因此它们在转化研究中的作用较小。因此,开发一种一致且简单的大型动物胶质瘤异种移植模型将对转化研究产生重大益处:方法:在 12 只标准尤卡坦小型猪中诱导免疫抑制。3头猪只接受环孢素治疗,9头猪接受包括环孢素(55 毫克/千克,q12 小时)、泼尼松(25 毫克,q24 小时)和霉酚酸酯(500 毫克,q24 小时)在内的联合疗法。将 U87 细胞(2 × 106)立体定向植入左侧额叶皮层。植入的大脑通过核磁共振成像进行监测。在另一项研究中,使用联合疗法在另外 5 头猪体内培育肿瘤,并在术中更新图像的情况下对猪进行肿瘤切除,以确定异种移植模型是否能准确捕捉人类所面临的肿瘤切除空间挑战:结果:11头猪成功植入并生长了肿瘤。仅使用环孢素组的一只动物未能显示临床肿瘤生长。通过核磁共振成像评估临床肿瘤生长情况,前10天肿瘤生长缓慢,随后10天肿瘤生长迅速。肿瘤生长的平均潜伏期为 20 天。在整个实验期间,每天对动物进行两次监测,并做详细记录。当肿瘤长到 1 - 2 厘米时,猪被人道处死。有些猪食欲下降,活动减少,但没有猪需要过早安乐死。在图像更新研究中,所有五头猪在开颅手术后都出现了脑转移,这与在人类身上观察到的情况一致。术中图像更新能够准确捕捉并纠正所有五头猪的这种偏移:本报告展示了在免疫抑制但非转基因猪体内开发和使用人类颅内胶质瘤模型的情况。虽然该模型的免疫抑制可能会限制其在某些研究中的应用,但该模型确实克服了小动物模型或转基因模型的一些局限性。例如,我们展示了如何利用该模型通过术中图像更新技术指导手术切除。我们进一步报告了颅外肿瘤替代物的使用情况,该替代物可显示颅内肿瘤的生长情况,从而无需放射成像即可进行相对生长评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Porcine-human glioma xenograft model. Immunosuppression and model reproducibility

Background

Glioblastoma is the most common primary malignant and treatment-resistant human brain tumor. Rodent models have played an important role in understanding brain cancer biology and treatment. However, due to their small cranium and tumor volume mismatch, relative to human disease, they have been less useful for translational studies. Therefore, development of a consistent and simple large animal glioma xenograft model would have significant translational benefits.

Methods

Immunosuppression was induced in twelve standard Yucatan minipigs. 3 pigs received cyclosporine only, while 9 pigs received a combined regimen including cyclosporine (55 mg/kg q12 h), prednisone (25 mg, q24 h) and mycophenolate (500 mg q24 h). U87 cells (2 × 106) were stereotactically implanted into the left frontal cortex. The implanted brains were imaged by MRI for monitoring. In a separate study, tumors were grown in 5 additional pigs using the combined regimen, and pigs underwent tumor resection with intra-operative image updating to determine if the xenograft model could accurately capture the spatial tumor resection challenges seen in humans.

Results

Tumors were successfully implanted and grown in 11 pigs. One animal in cyclosporine only group failed to show clinical tumor growth. Clinical tumor growth, assessed by MRI, progressed slowly over the first 10 days, then rapidly over the next 10 days. The average tumor growth latency period was 20 days. Animals were monitored twice daily and detailed records were kept throughout the experimental period. Pigs were sacrificed humanely when the tumor reached 1 - 2 cm. Some pigs experienced decreased appetite and activity, however none required premature euthanasia. In the image updating study, all five pigs demonstrated brain shift after craniotomy, consistent with what is observed in humans. Intraoperative image updating was able to accurately capture and correct for this shift in all five pigs.

Conclusion

This report demonstrates the development and use of a human intracranial glioma model in an immunosuppressed, but nongenetically modified pig. While the immunosuppression of the model may limit its utility in certain studies, the model does overcome several limitations of small animal or genetically modified models. For instance, we demonstrate use of this model for guiding surgical resection with intraoperative image-updating technologies. We further report use of a surrogate extracranial tumor that indicates growth of the intracranial tumor, allowing for relative growth assessment without radiological imaging.

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来源期刊
CiteScore
4.30
自引率
0.00%
发文量
148
审稿时长
56 days
期刊介绍: Cancer Treatment and Research Communications is an international peer-reviewed publication dedicated to providing comprehensive basic, translational, and clinical oncology research. The journal is devoted to articles on detection, diagnosis, prevention, policy, and treatment of cancer and provides a global forum for the nurturing and development of future generations of oncology scientists. Cancer Treatment and Research Communications publishes comprehensive reviews and original studies describing various aspects of basic through clinical research of all tumor types. The journal also accepts clinical studies in oncology, with an emphasis on prospective early phase clinical trials. Specific areas of interest include basic, translational, and clinical research and mechanistic approaches; cancer biology; molecular carcinogenesis; genetics and genomics; stem cell and developmental biology; immunology; molecular and cellular oncology; systems biology; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; cancer policy; and integration of various approaches. Our mission is to be the premier source of relevant information through promoting excellence in research and facilitating the timely translation of that science to health care and clinical practice.
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